Cachectin (tumor necrosis factor) is a macrophage hormone produced in response to endotoxin and strongly implicated in the pathogenesis of gram-negative shock. Cachectin biosynthesis is tightly regulated at transcriptional and translational levels, and several discrete stimuli for cachectin mRNA translation have been identified. In the studies proposed, a precise analysis of factors regulating cachectin gene expression will be undertaken through a combination of immunochemical, nucleic acid hybridization, and in vitro translation techniques. The mechanism of translational activation by endotoxin, interferon-gamma, and influenza virus will be studied. Similarly, the mechanism of translational suppression by glucocorticoids, and by the LPSd (endotoxin resistance) mutation, will be examined. Cytoplasmic factors are presumed to mediate translational suppression and activation in response to external stimuli. An attempt will be made to isolate and characterize these factors. A 3'-untranslated sequence ((TTATTTAT)n shared by messengers encoding several inflammatory mediators may be involved in translational control of gene expression. Once the cytoplasmic regulators have been isolated, the role of this conserved 3'-untranslated element will be considered. These studies should provide a detailed understanding of the regulation of genes specifying inflammatory mediators. This information will be of great value in the design of a rational therapeutic approach to shock, cachexia, and perhaps a variety of chronic inflammatory disorders as well. Moreover, the data collected in these studies will be of interest to clinical investigators involved in the administration of cachectin (tumor necrosis factor), interferon-gamma, and other cytokines as antineoplastic agents. The translational control mechanisms defined in this macrophage system may prove highly informative in the analysis of mammalian hormonal regulation in general.